Multiple repeat regions within mouse DUX recruit chromatin regulators to facilitate an embryonic gene expression program.

The embryonic transcription factor DUX regulates chromatin opening and gene expression in totipotent cleavage-stage mouse embryos, and its expression in embryonic stem cells promotes their conversion to 2-cell embryo-like cells (2CLCs) with extraembryonic potential. However, little is known regarding which domains within mouse DUX interact with particular chromatin and transcription regulators. Here, we reveal that the C-terminus of mouse DUX contains five uncharacterized ~100 amino acid (aa) repeats followed by an acidic 14 amino acid tail. Unexpectedly, structure-function approaches classify two repeats as 'active' and three as 'inactive' in cleavage/2CLC transcription program enhancement, with differences narrowed to a key 6 amino acid section. Our proximity dependent biotin ligation (BioID) approach identified factors selectively associated with active DUX repeat derivatives (including the 14aa 'tail'), including transcription and chromatin factors such as SWI/SNF (BAF) complex, as well as nucleolar factors that have been previously implicated in regulating the Dux locus. Finally, our mechanistic studies reveal cooperativity between DUX active repeats and the acidic tail in cofactor recruitment, DUX target opening, and transcription. Taken together, we provide several new insights into DUX structure-function, and mechanisms of chromatin and gene regulation.

p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models.

In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.

Promoting cardiovascular health and wellness among African-Americans: Community participatory approach to design an innovative mobile-health intervention.

BACKGROUND: Despite improvements in mortality rates over the past several decades, cardiovascular (CV) disease remains the leading cause of death for African-Americans (AAs). Innovative approaches through mobile health (mHealth) interventions have the potential to support lifestyle change for CV disease prevention among AAs. We aimed to translate a behavioral theory-informed, evidence-based, face-to-face health education program into an mHealth lifestyle intervention for AAs. We describe the design and development of a culturally relevant, CV health and wellness digital application (app) and pilot testing using a community-based participatory research (CBPR) approach with AA churches. METHODS: This mixed methods study used a 4-phase iterative development process for intervention design with the AA community. Phase 1 included focus groups with AA community members and church partners (n = 23) to gain insight regarding potential app end user preferences. In Phase 2, the interdisciplinary research team synthesized Phase 1 input for preliminary app design and content development. Phase 3 consisted of a sequential 3-meeting series with church partners (n = 13) for iterative app prototyping (assessment, cultural tailoring, final review). Phase 4, a single group pilot study among AA church congregants (n = 50), assessed app acceptability, usability, and satisfaction. RESULTS: Phase 1 focus groups indicated general and health-related apps preferences: multifunctional, high-quality graphics/visuals, evidence-based, yet simple health information and social networking capability. Phase 2 integrated these preferences into the preliminary app prototype. Phase 3 feedback was used to refine the app prototype for pilot testing. Phase 4 pilot testing indicated high app acceptability, usability, and satisfaction. CONCLUSIONS: This study illustrates integration of formative and CBPR approaches to design a culturally relevant, mHealth lifestyle intervention to address CV health disparities among AAs. Given the positive app perceptions, our study supports the use of an iterative development process by others interested in implementing an mHealth lifestyle intervention for racial/ethnic minority communities. TRIAL REGISTRATION: Clinicaltrials.gov NCT03084822.

Developing health communication messaging for a social marketing campaign to reduce tobacco use in pregnancy among Alaska Native women.

BACKGROUND: Despite the high prevalence of tobacco use during pregnancy among Alaska Native and American Indian (AI/AN) women, few efforts have focused on developing tobacco cessation interventions for this group. This paper describes development of messaging for a social media campaign targeting the entire community to reduce tobacco use in pregnancy (cigarette smoking and smokeless tobacco use including a homemade product known as Iqmik) among AN women, as part of a multi-component intervention. METHOD: The study (clinical trial registration #NCT02083081) used mixed methods with two rounds of assessments to develop and refine culturally relevant message appeals. Round 1 used qualitative focus groups and individual interviews (N=60), and Round 2 used quantitative survey interviews (N=52). Each round purposively sampled adult AN pregnant women, family/friends, and Elders in Western Alaska, and included tobacco users and non-users. Round 1 also assessed reasons for tobacco use in pregnancy. RESULTS: Qualitative findings generally converged with quantitative results to indicate that many participants preferred factual, loss-framed, visual concepts on how maternal tobacco use harms the fetus, newborn, and child; in contrast to spiritual or emotional appeals, or gain-framed messaging. Stress was indicated as a major reason for tobacco use in pregnancy and strategies to manage stress along with other health pregnancy targets (e.g., prenatal care) were suggested. CONCLUSIONS: This preliminary study suggests campaign messages targeting the entire community to reduce tobacco use in pregnancy among rural AN women should include factual messaging for being tobacco-free as well as focus on reducing stress and other healthy pregnancy targets.

Adolescents' preferences for social support for healthful eating and physical activity.

OBJECTIVE: This study explored adolescents' views on the sources and types of social support they would prefer when trying to eat more healthfully and be more active, as well as their opinions regarding means of enhancing social support in interventions. METHODS: A total of 28 adolescents (14 males, 14 females) ages 13 to 18 years participated in 4 focus groups that were stratified by gender and age to enhance participation. RESULTS: As expected, participants most readily named parents and friends as important sources of support and described wanting instrumental and emotional support from parents, companionship and emotional support from friends, and informational support from professionals. The focus groups revealed rich information regarding parents' and peers' behaviors that are and are not received as emotionally supportive, the helpfulness of parents' concurrent changes in lifestyle, and the importance of parents not ignoring or colluding with unhealthful behavior. Most participants expressed a need for frequent contact and a trusting relationship with professionals. Opinions were mixed regarding inclusion of others in appointments, use of electronic communications and social media, and group treatment formats. CONCLUSION: Results have implications for enhancing social support in behavioral weight management interventions that are developmentally relevant for adolescents.

Development of a tobacco cessation intervention for Alaska Native youth.

Tobacco cessation treatments have not been evaluated among Alaska Native (AN) adolescents. This pilot study evaluated the feasibility and acceptability of a targeted cessation intervention developed for AN youth. Intervention components were informed by prior focus groups assessing treatment preferences among AN youth, a social cognitive theoretical framework and feedback obtained from a teen advisory group. The intervention consisted of a weekend program where youth traveled by small airplane from their villages to stay overnight with other adolescents who quit tobacco use together. The program included recreational activities, talking circles, personal stories from elders and teen advisors, and cognitive behavioral counseling. Two intervention pilots were conducted from October 2010 to January 2011 using a non-randomized, uncontrolled study design with assessments at baseline and six-week follow-up. One village in Western Alaska was selected for each pilot with a targeted enrollment of 10 adolescents each. Participants were recruited for each pilot within five days, but recruitment challenges and ''lessons learned'' are described. The first pilot enrolled nine adolescents (all female) aged 13-16 years; all nine attended the intervention program and 78% (7/9) completed follow-up. The second pilot enrolled 12 adolescents (eight females, four males) aged 12-17 years, of which seven attended the intervention program. Six of these seven participants (86%) completed follow-up. In both pilots, participants rated the intervention as highly acceptable. A targeted cessation intervention was feasible and acceptable to AN youth. The intervention will be tested for efficacy in a subsequent randomized controlled trial.

The dynamic interplay between perceived true self-knowledge and decision satisfaction.

The present research used multiple methods to examine the hypothesis that perceived true self-knowledge and decision satisfaction are inextricably linked together by a widely held "true-self-as-guide" lay theory of decision making. Consistent with this proposition, Study 1 found that participants rated using the true self as a guide as more important for achieving personal satisfaction than a variety of other potential decision-making strategies. After establishing the prevalence of this lay theory, the remaining studies then focused on examining the proposed consequent relationship between perceived true self-knowledge and decision satisfaction. Consistent with hypotheses, 2 cross-sectional correlational studies (Studies 2 and 3) found a positive relationship between perceived true self-knowledge and decision satisfaction for different types of major decisions. Study 4 used daily diary methods to demonstrate that fluctuations in perceived true self-knowledge reliably covary with fluctuations in decision satisfaction. Finally, 2 studies directly examined the causal direction of this relationship through experimental manipulation and revealed that the relationship is truly bidirectional. More specifically, Study 5 showed that manipulating perceived knowledge of the true self (but not other self-concepts) directly affects decision satisfaction. Study 6 showed that this effect also works in reverse by manipulating feelings of decision satisfaction, which directly affected perceived knowledge of the true self (but not other self-concepts). Taken together, these studies suggest that people believe the true self should be used as a guide when making major life decisions and that this belief has observable consequences for the self and decision making.

Web-based intervention for adolescent nonsmokers to help parents stop smoking: a pilot feasibility study.

A novel approach to tobacco control is to engage adolescent nonsmokers in support roles to encourage and help their parents stop smoking. This pilot study examined the feasibility and potential efficacy of a web-based support skills training (SST) intervention for adolescents to help a parent stop smoking. Forty nonsmoking adolescents 13-19 years of age (70% female, 93% White) were enrolled and randomly assigned to a health education (HE) control group (n=20) or SST (n=20). Both consisted of written materials and five weekly, 30 min, web-based, counselor-facilitated group sessions. Parents were enrolled for assessments only. Adolescents and parents completed assessments at baseline, week 6 (post-treatment), week 12 and 6-months follow-up. Both interventions were feasible based on treatment acceptability ratings, study retention and treatment compliance. The biochemically confirmed 6-month smoking abstinence rate was higher for parents linked to teens in HE (35%, 7/20) than in SST (10%, 2/20), p=0.13. About half of parents in each group reported a quit attempt since study enrollment. Teens can be engaged to help parents stop smoking. Future research is warranted on determining effective intervention approaches.

A population-based study of prevalence and adherence trends in average risk colorectal cancer screening, 1997 to 2008.

BACKGROUND: Increasing colorectal cancer screening (CRCS) is important for attaining the Healthy People 2020 goal of reducing CRC-related morbidity and mortality. Evaluating CRCS trends can help identify shifts in CRCS, and specific groups that might be targeted for CRCS. METHODS: We utilized medical records to describe population-based adherence to average-risk CRCS guidelines from 1997 to 2008 in Olmsted County, MN. CRCS trends were analyzed overall and by gender, age, and adherence to screening mammography (women only). We also carried out an analysis to examine whether CRCS is being initiated at the recommended age of 50. RESULTS: From 1997 to 2008, the size of the total eligible sample ranged from 20,585 to 21,468 people. CRCS increased from 22% to 65% for women and from 17% to 59% for men (P < 0.001 for both) between 1997 and 2008. CRCS among women current with mammography screening increased from 26% to 74%, and this group was more likely to be adherent to CRCS than all other subgroups analyzed (P < 0.001).The mean ages of screening initiation were stable throughout the study period, with a mean age of 55 years among both men and women in 2008. CONCLUSION: Although overall CRCS tripled during the study period, there is still room for improvement. IMPACT: Working to decrease the age at first screening, exploration of gender differences in screening behavior, and targeting women adherent to mammography but not to CRCS seem warranted.

Perceptions of tuberculosis among immigrants and refugees at an adult education center: a community-based participatory research approach.

English as a Second Language programs serve large foreign-born populations in the US with elevated risks of tuberculosis (TB), yet little is known about TB perceptions in these settings. Using a community-based participatory research approach, we elicited perceptions about TB among immigrant and refugee learners and staff at a diverse adult education center. Community partners were trained in focus groups moderation. Ten focus groups were conducted with 83 learners and staff. Multi-level, team-based qualitative analysis was conducted to develop themes that informed a model of TB perceptions among participants. Multiple challenges with TB control and prevention were identified. There were a variety of misperceptions about transmission of TB, and a lack of knowledge about latent TB. Feelings and perceptions related to TB included secrecy, shame, fear, and isolation. Barriers to TB testing include low awareness, lack of knowledge about latent TB, and the practical considerations of transportation, cost, and work schedule conflicts. Barriers to medication use include suspicion of generic medications and perceived side effects. We posit adult education centers with large immigrant and refugee populations as excellent venues for TB prevention, and propose several recommendations for conducting these programs. Content should dispel the most compelling misperceptions about TB transmission while clarifying the difference between active and latent disease. Learners should be educated about TB in the US and that it is curable. Finally, TB programs that include learners and staff in their design and implementation provide greater opportunity for overcoming previously unrecognized barriers.

Support-person promotion of a smoking quitline: a randomized controlled trial.

BACKGROUND: Quitlines and other evidence-based cessation treatments are greatly underutilized by smokers, limiting their public health impact. Social support is correlated with successful cessation. Thus, efforts targeting the social network of smokers could be a potential avenue to promote quitline utilization. PURPOSE: This study examined the efficacy of an intervention for nonsmokers interested in helping a smoker (i.e., support people) to promote smoker utilization of the Minnesota QUITPLAN(®) Helpline. Data were collected from 2007 to 2010, and analyses were conducted from 2010 to 2011. DESIGN: Two-group randomized design evaluating the support-person intervention (n=267) compared with a control condition (written materials, n=267). SETTING/PARTICIPANTS: Enrolled were 534 support people (91% female, 93% Caucasian) residing in Minnesota. INTERVENTION: Written materials plus three weekly telephone sessions lasting 10-30 minutes each. Based on Cohen's theory of social support, the intervention provided participants with information and skills needed to encourage their smoker to call the QUITPLAN Helpline. MAIN OUTCOME MEASURES: Participants completed the Support Provided Measure (SPM) by mail at baseline and Week 4 (end-of-treatment). Helpline intake staff documented smoker calls to the Helpline through 6 months of follow-up. RESULTS: The proportion of calls to the Helpline was significantly (p=0.012) greater for smokers linked to support people in the intervention group (16.1%, 43/267) than in the control group (8.6%, 23/267). The treatment effect remained significant after adjusting for support person residing with the smoker (OR=2.04, 95% CI=1.19, 3.49, p=0.010). Among support people randomly assigned to the intervention group, greater number of sessions completed was associated with increased smokers' calls to the Helpline (p=0.004). After adjusting for the baseline score, the M±SD SPM score at Week 4 was significantly higher for support people in the intervention group (16.4±3.3) than for those in the control group (15.3±3.6), p=0.002. CONCLUSIONS: A support-person intervention is effective in increasing smoker utilization of the QUITPLAN Helpline. There is potential for increasing the reach of quitlines by targeting the social network of smokers. TRIAL REGISTRATION #: NCT01311830.

Healthy women's motivators and barriers to participation in a breast cancer cohort study: a qualitative study.

PURPOSE: This focus group study describes motivators and barriers to participation in the Mayo Mammography Health Study (MMHS), a large-scale longitudinal study examining the causal association of breast density with breast cancer, involving completion of a survey, providing access to a residual blood sample for genetic analyses, and sharing their results from a screening mammogram. These women would then be followed up long term for breast cancer incidence and mortality. METHODS: Forty-eight women participated in six focus groups, four with MMHS non-respondents (n = 27), and two with MMHS respondents (n = 21). Major themes were summarized using content analysis. Social cognitive theory (SCT) was used as a framework for interpretation of the findings. RESULTS: Barriers to participation among MMHS non-respondents were 1) lack of confidence in their ability to fill out the survey accurately (self-efficacy); 2) lack of perceived personal connection to the study or value of participation (expectancies); and 3) fear related to some questions about perceived cancer risk and worry/concern (emotional coping responses). Among MMHS respondents, personal experience with cancer was reported as a primary motivator for participation (expectancies). CONCLUSIONS: Application of a theoretical model such as social cognitive therapy to the development of a study recruitment plan could be used to improve rates of study participation and provide a reproducible and evaluable strategy.

Support person intervention to promote smoker utilization of the QUITPLAN Helpline.

BACKGROUND: Effective cessation services are greatly underutilized by smokers. Only about 1.5% of smokers in Minnesota utilize the state-funded QUITPLAN Helpline. Substantial evidence exists on the role of social support in smoking cessation. In preparation for a large randomized trial, this study developed and piloted an intervention for an adult nonsmoking support person to motivate and encourage a smoker to call the QUITPLAN Helpline. METHODS: The support person intervention was developed based on Cohen's theory of social support. It consisted of written materials and three consecutive, weekly, 20-30 minute telephone sessions. Smoker calls to the QUITPLAN Helpline were documented by intake staff. RESULTS: Participants were 30 support people (93% women, 97% Caucasian, mean age 49). High rates of treatment compliance were observed, with 28 (93%) completing all three telephone sessions. The intervention was ranked as somewhat or very helpful by 77% of the support people, and 97% would definitely or probably recommend the program. Five smokers linked to a support person called the QUITPLAN Helpline. CONCLUSIONS: An intervention using natural support networks to promote smoker utilization of the QUITPLAN Helpline is both acceptable to a support person and feasible. A controlled randomized trial is under way to examine the efficacy of the intervention.